Submissions for variant NM_020822.3(KCNT1):c.2849G>A (p.Arg950Gln)

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000498228	SCV000340255	uncertain significance	not provided	2016-03-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000498228	SCV000589673	pathogenic	not provided	2022-04-29	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a gain-of-function phenotype (Dilena et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29694806, 29056246, 26122718, 27029629, 29196578, 28488083, 29100083, 31487502, 30847371, 32167590, 30112700)
Invitae	RCV000650627	SCV000772474	pathogenic	Developmental and epileptic encephalopathy, 14; Autosomal dominant nocturnal frontal lobe epilepsy 5	2023-12-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 950 of the KCNT1 protein (p.Arg950Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with infantile seizures, epilepsy and developmental delay (PMID: 26122718, 27029629, 29100083). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 286710). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KCNT1 protein function with a negative predictive value of 80%. This variant disrupts the p.Arg950 amino acid residue in KCNT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV001004680	SCV001164136	pathogenic	Developmental and epileptic encephalopathy, 14	2017-02-15	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000498228	SCV001447907	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV001420735	SCV001623055	pathogenic	Seizure	2021-05-17	criteria provided, single submitter	clinical testing	missense variant absnet from gnomad. Previously described in the litterature. de novo
3billion	RCV001004680	SCV002572898	pathogenic	Developmental and epileptic encephalopathy, 14	2022-09-01	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000286710). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 26122718 , 27029629 , 29100083). A different missense change at the same codon (p.Arg950Leu) has been reported to be associated with KCNT1-related disorder (ClinVar ID: VCV000473378). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	RCV001004680	SCV002578112	likely pathogenic	Developmental and epileptic encephalopathy, 14	2022-09-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004021207	SCV004893013	pathogenic	Inborn genetic diseases	2023-10-26	criteria provided, single submitter	clinical testing	The c.2849G>A (p.R950Q) alteration is located in exon 25 (coding exon 25) of the KCNT1 gene. This alteration results from a G to A substitution at nucleotide position 2849, causing the arginine (R) at amino acid position 950 to be replaced by a glutamine (Q). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been detected in the heterozygous state in multiple individuals with clinical features of KCNT1-related neurodevelopmental disorder and has been determined to be the result of a de novo mutation multiple individuals (Bonardi, 2021; Borlot, 2020; Costain, 2019; Dilena, 2018; Hamdan, 2017; Hildebrand, 2016; Møller, 2015). In addition, this alteration was reported to cosegregate with disease in one family (Rubboli, 2019). This amino acid position is highly conserved in available vertebrate species. In vitro functional studies indicate this alteration leads to a shift in the half-activation voltage and support a gain-of-function impact on channel properties (Hinckley, 2023; Dilena, 2018). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.